Timoptic XE, a timolol ophthalmic gel-forming solution, is administered once daily.
The ophthalmic vehicle, gellan gum (Gelrite), is a solution that forms a clear gel in
the presence of monovalent or divalent cations.
25 This ion-activated gelation
prolongs precorneal residence time and increases ocular bioavailability, allowing
timolol to be administered once daily.
25 Timoptic XE is comparable to timoptic
lowering IOP. The incidence of adverse reactions, including decreases in heart rate,
is also comparable to that for timolol.
Another nonselective β-adrenergic blocking agent, metipranolol 0.1% to 0.6%, is
comparable to timolol 0.25% to 0.5% in reducing IOP.
8,9 Like timolol, metipranolol
produces corneal anesthesia, which occurs within 1 minute of instillation and returns
20 Metipranolol is associated with a greater incidence of
stinging or burning on administration and has been associated with granulomatous
28,29 As a result of these side effects, the use of metipranolol is
Carteolol, a nonselective β-adrenergic blocking agent with partial β-adrenergic
agonist activity, theoretically should minimize the bronchospastic, bradycardic, and
hypotensive effects associated with other ocular β-adrenergic blockers.
no clinical differences were seen when the cardiovascular and pulmonary function
effects of carteolol were compared with those of timolol. Carteolol 1% and timolol
0.25% administered BID are equally effective in reducing IOP.
In contrast to other β-adrenergic blocking ophthalmic agents, betaxolol is a selective
-adrenergic blocker. This cardioselective property may result in less adverse
effects on pulmonary function than nonselective β-adrenergic blockers in patients
with reactive airway disorders. Betaxolol is slightly less effective than timolol in
IOP reduction, and more patients tend to need adjunctive therapy with
Latanoprost (Xalatan), travoprost (Travatan Z), bimatoprost (Lumigan), and
tafluprost (Zioptan) are all PGAs. Latanoprost and travoprost, and tafluprost are
, and they lower IOP by serving as selective
-receptor agonists. Bimatoprost is a synthetic prostamide analog.
Tafluprost is a preservative-free formulation supplied in single-use containers.
The prostaglandin analogs increase uveoscleral outflow of aqueous humor and,
35 These agents often are prescribed as first-line agents for the
treatment of POAG because they are at least as effective as the β-blockers, can be
administered once a day, and are associated with minimal systemic adverse effects.
Latanoprost (Xalatan) is approved for the initial treatment of POAG or ocular
36 When administered once daily in the evening, latanoprost is at least
as effective as timolol in decreasing IOP. When the effectiveness of latanoprost
0.005% once daily was compared with timolol 0.5% BID, the IOP-lowering effects
of latanoprost were superior to those of timolol.
In addition, the nocturnal control
of IOP with latanoprost was superior to that with timolol. Latanoprost 0.005%
should be dosed once daily in the evening because the IOP-lowering effects of
latanoprost might actually be inferior when administered more frequently.
Systemic side effects are minimal with latanoprost, but local reactions (e.g., iris
pigmentation; eyelid skin darkening; eyelash lengthening, thickening, pigmentation,
and misdirected growth; conjunctival hyperemia; ocular irritation; superficial
punctate keratitis) are relatively common. Latanoprost can gradually increase the
amount of brown pigment in the iris by increasing the melanin content in the stromal
melanocytes of the iris. This pigment change occurs in 7% to 22% of patients and is
most noticeable in those with green-brown, blue/gray-brown, or yellow-brown
36 The onset of increased iris pigmentation usually is noticeable within the first
year of treatment and can be permanent. The nature and severity of adverse events are
not affected by the increased pigmentation of the iris.
Latanoprost has additive effects when administered with β-blockers (e.g., timolol),
carbonic anhydrase inhibitors (e.g., dorzolamide), and α2
brimonidine, apraclonidine). When added to existing therapy, latanoprost decreases
IOP an additional 2.9 to 6.1 mm Hg. As a result, latanoprost is a good adjunctive
ophthalmic agent for patients who are unable to adequately lower their IOP with
single-agent therapy. Although the complementary IOP-lowering effects of
latanoprost are comparable to those of brimonidine (at least a 15% reduction in IOP)
in patients inadequately controlled on β-adrenergic blocking agents, brimonidine (an
-adrenergic agonist) in a comparative study was associated with fewer adverse
effects on the quality of life. For example, watery or teary eyes and cold hands and
feet were reported more frequently in latanoprost-treated patients.
effectiveness of latanoprost when used once a day alone or as an adjunct to other
IOP-lowering drugs and its relative tolerability make it one of the most common if
not the most common treatment option for POAG and ocular hypertension.
Travoprost (Travatan Z) is US Food and Drug Administration (FDA)-approved for
the reduction of elevated IOP and ocular hypertension in patients who are intolerant
or who fail to respond to other agents. Travoprost is used as a first-line agent in
clinical practice because it is more effective than timolol and at least as effective as
latanoprost. The mean IOP reduction with travoprost in African-American patients
was 1.8 mm Hg greater than in non–African-American patients. Travoprost, as
adjunctive therapy to timolol in patients not responding adequately to timolol alone,
reduced IOP an additional 6 to 7 mm Hg. The side effect profile of travoprost is
similar to that for latanoprost, including increased iris pigmentation and eyelash
43–45 Local irritation may be less with travoprost because it is free of the
preservative benzalkonium chloride (BAK). Rather, travoprost is preserved in the
bottle with SofZia, which is a unique ionic buffer containing borate, sorbitol,
Like travoprost, bimatoprost (Lumigan) once daily or BID achieved lower target
IOPs than did timolol BID. Bimatoprost BID, however, was less effective than
bimatoprost once a day. Iris pigmentation changed in 1.1% of bimatoprost-treated
patients. In a 6-month randomized multicenter study, bimatoprost once a day lowered
IOP more effectively than latanoprost once a day. Side effects were similar between
treatment groups; however, conjunctiva hyperemia was more common (p < 0.001) in
bimatoprost-treated patients. Overall, the side effect profile of bimatoprost appears
to be similar to that for latanoprost and travoprost.
46–48 The local side effects seen
with other PGAs also appear to be relatively common with bimatoprost. As a result,
the FDA approved the cosmetic use of bimatoprost solution under the trade name
Latisse. Latisse solution is applied with an applicator to the base of the
upper eyelashes for the treatment of hypotrichosis (inadequate eyelashes). Eyelash
lengthening, thickening, and darkening or pigmentation is seen after 8 to 16 weeks of
Tafluprost (Zioptan) is a preservative-free product, US FDA-approved for the
reduction of elevated IOP and ocular hypertension. Tafluprost daily in the evening is
as effective as latanoprost daily in the evening and timolol 0.5% BID and has
demonstrated additive efficacy when administered with timolol. Switch studies
evaluating tafluprost in patients receiving BAK containing agents demonstrated some
improvement in adverse effects. As a result, tafluprost is an important option for
patients with a documented hypersensitivity to BAK or other PGAs. The adverse
effect profile is similar to other PGAs.
Apraclonidine (Iopidine) and brimonidine (Alphagan) are selective α2
agonists similar to clonidine. Apraclonidine is less lipophilic than clonidine and
brimonidine, does not cross the blood–brain barrier as readily, and theoretically has
fewer systemic side effects (e.g., hypotension, decreased pulse, dry mouth).
Brimonidine is more highly selective for α2
-adrenergic receptors than clonidine or
apraclonidine and, theoretically, should be associated with fewer ocular side effects.
-Adrenergic agonists appear to lower IOP by decreasing the production of aqueous
humor and by increasing uveoscleral outflow.
Brimonidine is an alternative first-line agent in the treatment of POAG. It may also
be used as adjunctive therapy in patients not responding to other agents.
Apraclonidine 1% is indicated to control or prevent postsurgical elevations in IOP
after argon laser trabeculoplasty or iridotomy. The 0.5% apraclonidine solution is
indicated for short-term adjunctive therapy in patients on maximally tolerated
medical therapy. Long-term IOP control should be monitored closely in patients
-adrenergic agonists because tachyphylaxis can occur. Common ocular side
effects include burning, stinging, blurring, conjunctival follicles, and an allergic-like
reaction consisting of hyperemia, pruritus, edema of the lid and conjunctiva, and
foreign body sensation. Although ocular side effects are less common with
brimonidine than with apraclonidine, systemic side effects (e.g., dry nose and mouth,
mild hypotension, decreased pulse, and lethargy) are more common with
-Adrenergic agonists should be used with caution in patients with
cardiovascular disease, orthostatic hypotension, depression, and renal or hepatic
55,56 Brimonidine (Alphagan P) is available with Purite as a preservative,
which facilitates drug delivery into the eye, allowing use of a lower drug
The IOP-reduction effects (peak and trough) of brimonidine 0.2% BID are 14% to
28%. Although the approved dosing schedule of brimonidine is 3 times a day (TID),
brimonidine 0.2% BID lowers IOP comparably to timolol 0.5% BID, and both are
slightly better than betaxolol 0.25% BID.
57,58 The IOP-lowering effect of brimonidine
also may be comparable to that of latanoprost; however, conflicting efficacy and
tolerability results in clinical studies may be related to differences in study design.
The combination of brimonidine and timolol is as equally tolerable and effective as
the combination of dorzolamide and timolol.
ophthalmic solution combines an α2
-adrenergic agonist (brimonidine tartrate 0.2%)
with a β-adrenergic blocker (timolol maleate 0.5%).
Topical Carbonic Anhydrase Inhibitors
Carbonic anhydrase occurs in high concentrations in the ciliary processes and retina
of the eye. Carbonic anhydrase inhibitors (CAIs) lower IOP by decreasing
bicarbonate production and, therefore, the flow of bicarbonate, sodium, and water
into the posterior chamber of the eye, resulting in a 40% to 60% decrease in aqueous
Although CAIs have been used orally for many years in the treatment of elevated
IOPs, they have been replaced by the topical ophthalmic CAIs, dorzolamide
(Trusopt) and brinzolamide (Azopt), which are safer and better tolerated. Topical
CAIs are excellent alternatives to β-blockers in the initial management of elevated
IOPs, and are effective as adjunctive agents. Brinzolamide 1% TID reduces IOP
comparably to that achieved with dorzolamide 2% TID and to betaxolol 0.5% BID,
but slightly less than timolol 0.5% BID. The IOP-reduction effects (peak and trough)
of dorzolamide 2% TID are 16% to 25%. Brinzolamide and dorzolamide are
approved for TID dosing; however, BID dosing may be adequate. Dorzolamide
provides additional IOP-lowering effects when added to existing β-blocker
61,62 An ophthalmic solution of dorzolamide hydrochloride and timolol
maleate is marketed as Cosopt, and a combination of brinzolamide and brimonidine
The combined use of topical dorzolamide and oral acetazolamide does not result
in additive effects and might increase the risk of toxicity. Therefore, the concomitant
use of topical and oral CAIs is not advised.
The topical CAIs are well tolerated with few systemic side effects. The most
common adverse effects reported with dorzolamide are ocular burning, stinging,
discomfort and allergic reactions, bitter taste, and superficial punctate keratitis.
Brinzolamide causes less burning and stinging of the eyes than dorzolamide, because
its pH more closely resembles that of human tears. Dorzolamide and brinzolamide
are sulfonamides and may cause the same types of adverse reactions attributable to
sulfonamides. These drugs should not be used in patients with renal or hepatic
Pilocarpine (Isopto Carpine) historically was an initial treatment of choice, but with
the introduction and widespread use of newer agents, pilocarpine has fallen out of
favor. Therapy usually is begun using lower concentrations (1%), one drop 4 times a
day (QID). Pilocarpine is a direct-acting cholinergic (parasympathomimetic) that
causes contraction of ciliary muscle fibers attached to the trabecular meshwork and
scleral spur. This opens the trabecular meshwork to enhance aqueous humor outflow.
There also may be a direct effect on the trabecular meshwork. Pilocarpine causes
miosis by contraction of the iris sphincter muscle, but the miosis is not related to the
Carbachol (Isopto Carbachol) is reserved as a third-line agent in patients who are
unresponsive or intolerant to initial medications. In addition to having direct
cholinergic effects, carbachol is more resistant to cholinesterase than pilocarpine.
Added benefits include increased release of acetylcholine from parasympathetic
nerve terminals and a weak anticholinesterase effect. Carbachol is administered TID.
If control of IOP is not achieved with optimal use of other topical monotherapy and
combination therapy agents, then anticholinesterase agents may be prescribed as a
last topical therapy option. Anticholinesterase agents inhibit the enzyme
cholinesterase, thereby increasing the amount of acetylcholine and its naturally
occurring cholinergic effects.
Echothiophate iodide (phospholine iodide), an irreversible cholinesterase inhibitor,
primarily inactivates pseudocholinesterase and secondarily inhibits true
cholinesterase. Echothiophate iodide
may be used if maximal doses of other agents and combination therapy are
ineffective. Echothiophate iodide has a long duration of action that affords good
control of IOP; however, miosis and myopia are significant side effects.
Concentrations higher than 0.06% are associated with a significant increase in
subjective complaints (e.g., brow ache).
In general, drugs with different pharmacologic actions have at least partially additive
effects in lowering IOP in the treatment of glaucoma. Drugs with similar
pharmacologic actions (i.e., from the same pharmacologic class) should not be
combined because dose-related adverse effects are more likely and the incremental
increase in benefits is likely to be more modest.
Timolol and other β-adrenergic blocking drugs have additive IOP-lowering effects
when used in combination with miotic agents, prostaglandin analogs, α2
CAIs. For example, the IOP-lowering effect is greater when timolol is used in
combination with pilocarpine, dorzolamide, brimonidine, and travoprost. Likewise,
for example, latanoprost has additive effects when administered with timolol,
68–73 The trend toward the development
of fixed-combination products offers many advantages in the treatment of POAG.
These advantages include improved adherence because of a reduction in the number
of dosages and bottles, eliminating the need to instill two separate drugs 5 to 10
minutes apart to prevent a washout effect from the second medication, improving
safety and tolerability by limiting the exposure to the BAK preservative, and a cost
savings for the patient by potentially eliminating a copay for one of the medications.
There are two β-adrenergic blocker combination products currently on the market,
those of latanoprost monotherapy.
65 Brinzolamide and brimonidine are combined and
QUESTION 1: M.H., a 52-year-old African-American woman with brown eyes, presented for routine
medications include the following:
Amitriptyline, 75 mg at bedtime
Chlorpheniramine, 4 mg every 6 hours as needed (PRN)
Nitroglycerin, 0.3 mg sublingual PRN
Fluticasone/salmeterol 250/50 mcg dry powder inhaler, one inhalation twice daily
Albuterol 90 mcg metered-dose inhaler, 1 to 2 puffs QID PRN
Tiotropium bromide inhaler, 18 mcg inhaled once daily
Findings on examination indicate that M.H. has POAG. What other factors may predispose M.H. to an
POAG is thought to be determined genetically, and M.H. has a positive family
history. The disease is more prevalent and aggressive in African-Americans.
addition, she is taking several medications that have been associated with increases
Most reports dealing with drug-induced increases in IOP center around precipitation
of angle-closure glaucoma by ophthalmic mydriatic or cycloplegic agents
(anticholinergics). In patients with open-angle glaucoma, topical anticholinergics can
significantly increase resistance to aqueous humor outflow and elevate IOP while the
anterior chamber remains grossly open.
4 As part of any routine ophthalmic
examination, the pupils are dilated with a mydriatic or cycloplegic agent (unless
otherwise contraindicated). The IOP is always measured before this procedure, so
the use of these agents would not have influenced the IOP readings in M.H.
If systemic anticholinergic agents are administered in doses sufficient to cause
pupillary dilation, the risk of precipitating angle-closure increases. However, it is
unlikely that these agents will aggravate open-angle glaucoma unless the amount
reaching the eye is sufficient to cause cycloplegia.
4 Although literature documentation
of POAG exacerbation by these agents is scarce, medications with anticholinergic
side effects (e.g., antihistamines, benzodiazepines, disopyramide, phenothiazines,
tricyclic antidepressants, tiotropium) should be considered. M.H. is receiving
chlorpheniramine as needed, amitriptyline at bedtime, and tiotropium bromide once
daily, but her pupil examination is normal with no evidence of mydriasis or
cycloplegia. Therefore, it is highly unlikely that these medications contributed to her
Adrenergic agents, such as central nervous system stimulants, vasoconstrictors,
appetite suppressants, and bronchodilators, may produce minimal pupillary dilation.
These have no proven adverse influences on IOP in patients with either normal eyes
or eyes with open-angle glaucoma. Consequently, the use of salmeterol and albuterol
in M.H. is also an unlikely source of the increased IOP.
Conclusive evidence for the production of angle-closure glaucoma by vasodilators is
lacking, although slight increases in IOP have been reported. Use of nitroglycerin as
needed in M.H. is not a cause for concern. There have been isolated reports of other
medications causing mydriasis in glaucoma patients. These include muscle relaxants
(carisoprodol), monoamine oxidase inhibitors, fenfluramine, ganglionic blocking
agents, salicylates, and oral contraceptives. Succinylcholine, ketamine, and caffeine
have been associated with increases in IOP. Corticosteroid-induced IOP elevation
will be addressed in Case 54-8, Question 2. If M.H. requires administration of any
other medications associated with increases in IOP, the risk of potential adverse
effects can be minimized by routine follow-up.
CASE 54-1, QUESTION 2: What is the best initial therapeutic treatment in M.H.?
Topical β-blockers or PGAs are the initial agents of choice in the treatment of
POAG (Fig. 54-2). Their efficacy is well documented in numerous studies, and side
effects are well characterized. Brimonidine (Alphagan) and topical CAIs are
alternative first-line agents. Table 54-1 lists the common topical agents used in the
Timolol or other nonselective β-adrenergic blockers should not be initiated for
M.H. because of her history of asthma (the indications and use of β-blockers for
patients with heart failure are described in Chapter 14, Heart Failure). Betaxolol, a
-adrenergic blocker, is better tolerated than the nonselective β-adrenergic blocker,
timolol, in patients with reactive airway disease and should be considered when
topical β-blocker therapy is indicated in patients such as M.H.
0.25% suspension BID would be reasonable for the initial treatment of M.H.’s
glaucoma. Nevertheless, adverse pulmonary and cardiac side effects can occur with
betaxolol: M.H. should be followed up closely for these adverse effects. Although
ocular burning and stinging have been associated more frequently with betaxolol and
metipranolol than with other topical β-blockers, the 0.25% suspension is better
tolerated than the 0.5% solution and is as effective.
31 Brimonidine, a topical CAI, and
a PGA (e.g., latanoprost) are acceptable alternatives to betaxolol as initial therapy.
Although brimonidine, topical CAIs, and latanoprost may not exacerbate her asthma
or CHF, they can cause localized side effects and brimonidine can cause systemic
Figure 54-2 Medical management of glaucoma. IOP, intraocular pressure; NLO, nasolacrimal occlusion.
Common Topical Agents Used in the Treatment of Open-Angle Glaucoma
Generic Mechanism Strength Usual Dosage Comments
associated ocular side effects.
compliance. Considered βblocker of choice in patients
Sympatholytic 1% 1 drop BID Effective with few associated
Sympatholytic 0.25%, 0.5% 1 drop daily or
ocular side effects. Daily and
Sympatholytic 0.3% 1 drop BID Effective with few associated
ocular side effects. Daily and
effectiveness, with welldefined side effect profile
Sympatholytic 0.25%, 0.5% 1 drop daily Once-daily timolol
vehicle, gellan gum (Gelrite),
bioavailability, allowing oncedaily administration
α2-Selective Adrenergic Agonists
Sympathomimetic 0.5%, 1% 1 drop
Sympathomimetic 0.15%, 0.2% 1 drop BID to
Sympathomimetic 0.1%, 0.15% 1 drop BID to
Topical Carbonic Anhydrase Inhibitors
1% 1 drop TID Shake suspension well
before use. Effective longterm monotherapy or
2% 1 drop TID Effective long-term
effective in AfricanAmericans. Does not
Prostamide 0.01%, 0.03% 1 drop once a day
Parasympathomimetic 1%, 2%, 4% 1–2 drops TID or
effectiveness. Little rationale
Parasympathomimetic 1.5%, 3% 1–2 drops TID or
or intolerant of other miotics.
Anticholinesterase 0.125% 1 drop BID Long duration, although
Sympathomimetic/sympatholytic 0.2%/0.5% 1 drop BID Combination products
1 drop BID Combination products
instillation of drops Brinzolamide
1%/0.2% 1 drop TID Shake suspension well
bedtime; GFS, gel-forming solution; QID, 4 times a day; TID, 3 times a day.
CASE 54-1, QUESTION 3: Betaxolol 0.25% suspension, one drop in both eyes BID, is ordered for M.H.
M.H. should be instructed to hold the inverted betaxolol bottle between her thumb
and middle finger and to rest that hand on her forehead to minimize the risk of
inadvertent eye injury caused by sudden unexpected movement of the hand. The index
finger is left free to depress the bottom of the container, releasing one drop for the
dose. With a little practice, this technique is easy to master. The lower eyelid should
be drawn downward with the index finger of the opposite hand or pinched between
the thumb and index finger to form a pouch. The patient should look up and
administer the drug into the pouch of the eye.
Patients must be encouraged to continue regular use of their medications for
effective treatment of glaucoma. Chronic glaucoma is a silent disease and often not
associated with symptoms; therefore, the continuation of therapy should be
encouraged continuously in patients, especially when side effects to drug therapy can
be encountered. Betaxolol is best administered every 12 hours because this schedule
of administration is consistent with its duration of action (see Table 54-1).
Systemic side effects (e.g., bradycardia, heart block, CHF, pulmonary distress,
central nervous system) are rare with betaxolol, but M.H. should be instructed to
report any of these effects to her primary-care provider.
CASE 54-1, QUESTION 4: How much would occlusion of the nasolacrimal ducts (punctal occlusion) by
M.H. influence systemic absorption or alter the therapeutic effects of betaxolol?
Nasolacrimal, or punctal, occlusion is a technique that can decrease the amount of
75 Occlusion of the puncta (through the application of
slight pressure with the finger to the inner corner of the eye closest to the nose for 3
to 5 minutes during and after drug instillation) can minimize systemic absorption of
ophthalmic medications (e.g., betaxolol), decrease the incidence of side effects, and
improve medication effectiveness.
75–77 When a single drop of ophthalmic timolol
0.5% was instilled into the eyes of patients at various times before cataract surgery
and the nasolacrimal duct was occluded for 5 minutes, drug levels in the aqueous
humor were significantly greater in patients who had their nasolacrimal ducts
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